Malignant tumors represented by carcinoma are diseases caused by abnormal growth of cells, and the most distinctive characteristic of malignant tumors is invasion into the surrounding tissue and metastasis to other organs. It has been long known that the leading cause of death for malignant tumor patients is not the growth of the primary lesion but multiple organ failure resulting from distant metastasis of the tumor cells. However, control of malignant tumor metastasis has not yet been achieved so far and is one of the most crucial issues in the whole area of cancer treatment.
Metastasis of an epithelial malignant tumor (carcinoma) is considered to be caused by various physiological phenomena of cancer cells, such as the acquisition of motility and migrating ability typified by epithelial to mesenchymal transition (hereinafter, abbreviated to “EMT”), invasion into the surrounding tissue, migration and invasion into blood vessels and lymphatic vessels, colonization in vascular endothelium of distant tissue, metastatic lesion formation, etc.
Also in a non-epithelial malignant tumor (sarcoma etc.), tumor cells that have become malignant and acquired motility and migrating ability invade blood vessels etc., colonize vascular endothelium of distant tissue, invade the tissue, and then form a metastatic lesion.
In this process, interaction between endothelial selectins of blood vessels, in particular capillary vessels, and selectin ligands expressed on tumor cells is involved in the colonization of circulating tumor cells in vascular endothelium (Non Patent Literature 1). It is also known that inflammatory cytokines (IL-1β, TNF-α) promote the adhesion of tumor cells to vascular endothelium (Non Patent Literature 2 and 3). For example, inflammatory cytokines produced by surgery or a surgery-induced infection systemically and locally promote the adhesion of tumor cells to vascular endothelium and facilitate the metastasis of the tumor cells to distant tissue and tumor recurrence at the primary site (Non Patent Literature 1 to 3).
In the prevailing pharmacological treatment for cancer, an anticancer/antitumor agent is administered to a tumor-bearing patient usually for the purpose of reducing the size of the primary focus, and the effect of the anticancer/antitumor agent is judged by the reduction percentage. However, an anticancer/antitumor agent is often harmful to normal tissue, and so-called “adverse effects” that cause various organ disorders appear at a high rate. Therefore, chronic dosing thereof causes problems of such serious side effects. For this reason, in actual cancer treatment, the administration of anticancer/antitumor agents has often to be restricted in terms of the amount and duration, leading to shortened life expectancy.
Ghrelin is a hormone found in the stomach in 1999. For example, the ghrelin of a mammal, such as a human, is a peptide having an amino acid sequence composed of 28 residues and having an extremely rare chemical structure in which the 3rd amino acid from the N terminus in the sequence is acylated with a fatty acid (Non Patent Literature 4 and Patent Literature 1).
Ghrelin is an endogenous cerebral-gastrointestinal hormone that acts on a growth hormone secretagogue-receptor 1a (GHS-R1a) and thereby promotes secretion of a growth hormone (GH) from the pituitary (Non Patent Literature 4 and 5).
Recent studies have revealed that ghrelin increases appetite, that subcutaneous administration of ghrelin increases body weight and body fat, and that ghrelin has activities such as improvement of cardiac function (Non Patent Literature 6 to 10). Further, since ghrelin has GH secretion promoting activity and appetite stimulation activity, it is expected that ghrelin, through the activity of GH, further effectively exerts fat-burning activity for converting fat into energy and the effect of strengthening muscles through the anabolic activity of GH (Non Patent Literature 11).
Adrenomedullin (hereinafter sometimes referred to as “AM”) is a peptide having a strong vasodilating effect. It was first isolated from human pheochromocytoma, and later immunoreactive AM was detected in various tissues including lung tissue (Non Patent Literature 12 to 14). AM receptor expression is abundant in the basal cells of the airway epithelium and Type II pneumocytes, and the two cell types are involved in epithelial regeneration of the lung (Non Patent Literature 15). In recent studies, it has been shown that AM activates, in vascular endothelial cells, the phosphatidylinositol 3-kinase/Akt dependent pathway, which is considered to regulate many essential steps for cell growth (Non Patent Literature 16 to 19).
Angiotensin II has an effect of, via angiotensin II receptors on cell membrane, constricting blood vessels to raise blood pressure. Therefore, an angiotensin II receptor antagonist can be an effective treatment agent for circulatory diseases, such as hypertension. A known example of a preferable chemical structure which exhibits a strong angiotensin II antagonistic effect is a structure having a biphenyl group substituted with a tetrazolyl group, a carboxyl group, or the like on the side chain. Pharmaceutical compounds having such a structural feature, for example, losartan, candesartan cilexetil, olmesartan medoxomil, etc. are clinically used as a treatment agent for hypertension (Non Patent Literature 20, Patent Literature 2 and 3, etc.).
HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase inhibitor specifically inhibits HMG-CoA reductase, which is a rate-limiting enzyme of biosynthesis of cholesterol. It is known that HMG-CoA reductase inhibitor, which suppresses the synthesis of cholesterol, is effective in the treatment of hypercholesterolemia, hyperlipoproteinemia, atherosclerosis, etc. (Non Patent Literature 21).
Known examples of the 1st generation of HMG-CoA reductase inhibitor include mevinolin, pravastatin, simvastatin, etc., which are a fungal metabolite or a partially modified product thereof (Patent Literature 4 to 6). After the emergence of the 1st generation drugs, synthetic HMG-CoA reductase inhibitors, such as fluvastatin, were developed, which are known as 2nd generation (Non Patent Literature 22 and Patent Literature 7).
However, it has been unknown that ghrelin, adrenomedullin, and HMG-CoA reductase inhibitors suppress the metastasis of malignant tumor cells (especially that they suppress the metastasis of a malignant tumor without targeting the malignant tumor itself).
Meanwhile, Non Patent Literature 23 describes, regarding angiotensin II receptor antagonists, that losartan suppressed the lung metastasis of renal cell carcinoma increased by cyclosporin (Cs). Non Patent Literature 24 describes that losartan suppressed the liver metastasis of colon cancer cells. Non Patent Literature 25 describes that candesartan suppressed the lung metastasis of renal cell carcinoma by inhibiting tumor angiogenesis and vascular endothelial growth factor (VEGF) expression. Non Patent Literature 26 describes that candesartan suppressed the lung and liver metastasis of osteosarcoma. Non Patent Literature 27 describes that candesartan cilexetil (TCV-116) suppressed the angiogenesis and metastasis of a tumor. Non Patent Literature 28 describes that angiotensin II type 1 receptor (AT1 receptor) system is involved in the growth, angiogenesis, and metastasis of a tumor.
Also, Non Patent Literature 29 describes that lovastatin as a HMG-CoA reductase inhibitor inhibits E selectin expression and inhibits the adhesion of colon cancer cells to human umbilical vein endothelial cells (HUVECs).
Patent Literature 8 discloses medicines for suppressing or preventing the metastasis of a malignant tumor, the medicines comprising, as an active ingredient, vascular endothelial intracellular cGMP enhancers, such as natriuretic peptide receptor GC-A agonist, but does not disclose the effects of ghrelin, adrenomedullin, angiotensin II receptor antagonists, and HMG-CoA reductase inhibitors on the metastasis of a malignant tumor.